title: Central activation of the cholinergic anti-inflammatory pathway reduces surgical inflammation in experimental post-operative ileus.
abstract: OBJECTIVE
  Electrical stimulation of the vagus nerve reduces intestinal inflammation following mechanical handling, thereby shortening post-operative ileus in mice. Previous studies in a sepsis model showed that this cholinergic anti-inflammatory pathway can be activated pharmacologically by central administration of semapimod, an inhibitor of p38 mitogen-activated protein kinase. We therefore evaluated the effect of intracerebroventricular (i.c.v.) semapimod on intestinal inflammation and post-operative ileus in mice.
  
  
  METHODS
  Mice underwent a laparotomy or intestinal manipulation 1 h after i.c.v. pre-treatment with semapimod (1 µg·kg(-1) ) or saline. Drugs were administered through a cannula placed in the left lateral ventricle 1 week prior to experimentation. Twenty-four hours after surgery, gastric emptying was measured using scintigraphy, and the degree of intestinal inflammation was assessed. Finally, activation of brain regions was assessed using quantitative immunohistochemistry for c-fos.
  
  
  RESULTS
  Intestinal manipulation induced inflammation of the manipulated intestine and significantly delayed gastric emptying, 24 h after surgery in saline-treated animals. Semapimod significantly reduced this inflammation and improved gastric emptying. Vagotomy enhanced the inflammatory response induced by intestinal manipulation and abolished the anti-inflammatory effect of semapimod. Semapimod but not saline induced a significant increase in c-fos expression in the paraventricular nucleus, the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve.
  
  
  CONCLUSIONS
  Our findings show that i.c.v. semapimod reduces manipulation-induced intestinal inflammation and prevented post-operative ileus. This anti-inflammatory effect depends on central activation of the vagus nerve.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Fo
authors.initials: F
authors.lastname: The
authors.forename: C
authors.initials: C
authors.lastname: Cailotto
authors.forename: J
authors.initials: J
authors.lastname: van der Vliet
authors.forename: W J
authors.initials: WJ
authors.lastname: de Jonge
authors.forename: R J
authors.initials: RJ
authors.lastname: Bennink
authors.forename: R M
authors.initials: RM
authors.lastname: Buijs
authors.forename: G E
authors.initials: GE
authors.lastname: Boeckxstaens
mesh_terms: D000109:Acetylcholine / Q000819:agonists*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004751:Enteritis / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D006835:Hydrazones / Q000008:administration & dosage / Q000627:therapeutic use*; D045823:Ileus / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007276:Injections, Intraventricular; D051379:Mice; D008807:Mice, Inbred BALB C; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D011183:Postoperative Complications / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism; D000813:Anilides; D006146:Guanidines
chemical_list: D000109:Acetylcholine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006835:Hydrazones; D016760:Proto-Oncogene Proteins c-fos; C097256:semapimod; D000813:Anilides; D006146:Guanidines